Nano & Microparticle Drug Delivery:

How will it play a role in peripheral arterial interventions

Subhash Banerjee, MDAssociate Prof. of MedicineUT Southwestern Med. Ctr.

Nov. 2013

Drug Coated Balloon (DCB)for Peripheral Arterial Interventions

Success of DCB relies on the rapid transfer of a single dose of an anti-proliferative agent into the vessel wall

The dominant challenge for DCB is rapid, uniform, efficient, & directed transfer of the drug to the vessel wall during balloon inflation with limited downstream distribution

Tissue delivery=8.8±3.9% of the mean percentage of total original catheter load

Cremers et al. Thromb Haemost. 2009; 101: 201–206

Drug-Coated Balloon Manufacturer Drug Carrier Drug Dose Density (µg/mm²)

Cotavance MEDRAD Paccocath Paclitaxel 3

SeQuent Please B. Braun Melsungen AG Paccocath Paclitaxel 3

IN. PACT Medtronic-Invatec FreePac Paclitaxel 3.5

Dior, Freeway Eurocor Shellac Paclitaxel 3

Moxy Lutonix-Bard Nonpolymeric Paclitaxel 2

Pantera Lux Biotronik Butyryl-tri-hexyl citrate Paclitaxel 3

AngioSculpt AngioScore unkonwn Paclitaxel 3

Protege Blue Medical unknown Paclitaxel 3

Elutax Aachen Resonance No (2 layers of paclitaxel) Paclitaxel 2

Wombat Avidal Vascular No (paclitaxel wrapped) Paclitaxel 3.3

Magic Touch Concept Medical Phospholipid based excipient Sirolimus 1.2

Drug Concentration of Current DCB

Waxman et al. JACC Cardiovasc Interv.2012; 5:1001-12

DCB 6x60 mm; 1 inflation=3391µg

Paclitaxel coated balloon=

Low-dose (0.2 μg/stent)

Intermediate-dose (15 μg/stent)

High-dose (187 μg/stent)Heldman et al. Circulation. 2001; 103: 2289-2295

Multi-Ligand Nanoparticles (MLNP)

Paclitaxel

“Platelet mimicking”

Poly (L-lactic-co-glycolic acid) (PLGA)

Surface conjugated ligands: polyethylene glycol (PEG) glycoprotein 1b (GP1b) trans-activating

transcriptional peptide (TAT) Extensive biocompatibility

testing

Banerjee et al. J Cardiovasc Transl Res. 2013 Aug;6(4):570-8

MLNP Uptake by Injured Endothelial Cells (EC)

Banerjee et al. J Cardiovasc Transl Res. 2013 Aug;6(4):570-8

PLGA-PEG PLGA-PEG-Gp1b PLGA-PEG-Gp1b/TAT

Under flow conditions

EC delivery

Drug Delivering MLNP Coated Balloon

Xu Hao et al. TCT 2013

Fluorescent Image of Nanoparticle-coated Angioplasty Balloon Tip

Nanoparticle-coated balloon surface after

inflation/deflation

Uncoated angioplasty balloon surface

Nanoparticle-coated balloon surface before inflation

Surface SEM of Nanoparticle-coated Angioplasty Balloon

Transfer of MLNP Coated Angioplasty Balloon to Rat Artery

Banerjee et al. J Cardiovasc Transl Res. 2012 Aug;5(4):519-27

A. Angioplasty balloon without coating of nanoparticles

B. Angioplasty balloon coated with nanoparticles before inflation

C. Angioplasty balloon coated with nanoparticles after inflation-deflation

D. Rat carotid artery before angioplasty

E. Rat carotid artery after angioplasty

7% particles were transferred to the artery wall

27% particles were lost

Paciltaxel-Loaded MLNP Suppresses Rat Carotid Artery Neointima

Banerjee et al. J Cardiovasc Transl Res. (in submission)

Uninjured Normal saline Nanoparticles w/o paclitaxel

Paclitaxelsolution

Paclitaxel-loaded

nanoparticle

Rat Carotid Balloon Injury Model

Paciltaxel-Loaded MLNP Suppresses Rat Carotid Artery Neointima

Banerjee et al. J Cardiovasc Transl Res. (in submission)

Rat Carotid Balloon Injury Model

IN. PACT

Wombat

Cotavance

SeQuent Please

Dior, Freeway

Pantera Lux

AngioSculpt Scoring

Protege

Moxy

Elutax

Magic Touch

Nanoparticle incorporated

0 0.5 1 1.5 2 2.5 3 3.5 4

3.5

3.3

3

3

3

3

3

3

2

2

1.2

0.4

Drug dosage density on balloon (mcg/mm2)

Drug Concentration of DCB

MLNP Loaded DCB for Peripheral Arterial Interventions

Paclitaxel containing biodegradable, MLNP can be loaded on angioplasty balloons & delivered reliably to injured vascular surfaces with demonstrable suppression of neointimal proliferation

MLNP-DCB may potentially offer a pathway for targeted drug delivery to injured vascular wall, at significantly reduced doses

Future studies to refine the technology, assess comparative efficacy & safety are on-going